Imines with alkenes

The groups of Loupy and Jun have presented a chelation-assisted rhodium(I)-cata-lyzed ortho-alkylation of aromatic imines with alkenes (Scheme 6.57) [119]. The use of 2 mol% of Wilkinson s catalyst, RhCl(PPh3)3, and 5 equivalents of the corresponding alkene under solvent-free conditions proved to be optimal, providing the desired ortho-alkylated ketones in high yields after acidic hydrolysis. Somewhat lower yields were obtained when the imine preparation and the ortho-alkylation were realized in a one-pot procedure. 

Michael addition of methylene imines with alkenes under solid Iiquid two-phase conditions provides a route to substituted a-amino acids [26, 27] (Scheme 6.22). When ethyl glycine is (V-protected with (S)-menthone, C-alkylation under soliddiquid... 

Thus, catalytic asymmetric aza Diels-Alder reactions of imines with alkenes have been developed using a chiral lanthanide Lewis acid, to afford 8-hydroxy-quinoline derivatives in high yields with high diastereo- and enantioselectivi-ties. Characteristic points of this reaction are as follows. 

Dipolar cycloadditions of nitrile imines with alkenes lead to 2-pyrazolines. Moderate select vities are observed in reactions with the acrylate of (/ )-pantolactone. 

Thus, we have developed catalytic asymmetric aza Diels-Alder reactions of imines with alkenes using a chiral lanthanide Lewis acid, to afford 8-hydroxyquinoline derivatives in high yields with high diastereo- and enan-tioselectivities. The characteristic points of this reaction are as follows, (i) Asymmetric aza Diels-Alder reactions between achiral azadienes and dienophiles have been achieved using a catalytic amount of a chiral source, (ii) The unique reaction pathway, in which the chiral Lewis acid activates not dienophiles but dienes, is revealed. In most asymmetric Diels-Alder reactions reported using chiral Lewis acids, the Lewis acids activate dienophiles [64, 65]. However, inverse electron-demand asymmetric Diels-Alder reactions of 2-pyrone derivatives have been reported [72]. (iii) A unique lanthanide complex including an azadiene and an additive, which is quite different from the conventional chiral Lewis acids, has been developed. 

In a manner analogous to classic nitrile iinines, the additions of trifluoro-methylacetonitrile phenylimine occur regiospecifically with activated terminal alkenes but less selectively with alkynes [39], The nitnle imine reacts with both dimethyl fumarate and dimethyl maleate m moderate yields to give exclusively the trans product, presumably via epimenzation of the labile H at position 4 [40] (equation 42) The nitrile imine exhibits exo selectivities in its reactions with norbornene and norbornadiene, which are similar to those seen for the nitrile oxide [37], and even greater reactivity with enolates than that of the nitnle oxide [38, 41], Reactions of trifluoroacetomtrile phenyl imine with isocyanates, isothiocyanates, and carbodiimides are also reported [42]... 

Reaction of a,/MJnsaturated Fischer Carbene Complexes with Alkenes, Butadienes, Enamines, and Imines... 

Abstract The photoinduced reactions of metal carbene complexes, particularly Group 6 Fischer carbenes, are comprehensively presented in this chapter with a complete listing of published examples. A majority of these processes involve CO insertion to produce species that have ketene-like reactivity. Cyclo addition reactions presented include reaction with imines to form /1-lactams, with alkenes to form cyclobutanones, with aldehydes to form /1-lactones, and with azoarenes to form diazetidinones. Photoinduced benzannulation processes are included. Reactions involving nucleophilic attack to form esters, amino acids, peptides, allenes, acylated arenes, and aza-Cope rearrangement products are detailed. A number of photoinduced reactions of carbenes do not involve CO insertion. These include reactions with sulfur ylides and sulfilimines, cyclopropanation, 1,3-dipolar cycloadditions, and acyl migrations. 

One of the earliest reported thermal reactions of Fischer carbene complexes was the reaction with olefins to give cyclopropanes [127]. More recently it has been shown that photolysis accelerates inter molecular cydopropanation of electron-poor alkenes [128]. Photolysis of Group 6 imine carbenes with alkenes... 

Table 25 Photo-driven reaction of Group 6 imine carbenes with alkenes ...

An alternative preparation of aziridines reacts an alkene with iodine and chloramine-T (see p. 1056) generating the corresponding A-tosyl aziridine. Bromamine-T (TsNBr Na ) has been used in a similar manner." Diazoalkanes react with imines to give aziridines." Another useful reagent is NsN=IPh, which reacts with alkenes in the presence of rhodium compounds or Cu(OTf)2 to give N—Ns aziridines. Manganese salen catalysts have also been used with this reagent. ... 

As in the case of Diels-Alder reactions, aqueous aza-Diels-Alder reactions are also catalyzed by various Lewis acids such as lanthanide triflates.113 Lanthanide triflate-catalyzed imino Diels-Alder reactions of imines with dienes or alkenes were developed. Three-component aza-Diels-Alder reactions, starting from aldehyde, aniline, and Danishefsky s diene, took place smoothly under the influence of HBL4 in aqueous media to afford dihydro-4-pyridone derivatives in high yields (Eq. 12.46).114... 

In addition to undergoing cycloaddition reactions with alkenes and al-kynes, silenes readily undergo cycloaddition reactions with heteroatom multiple bonds such as C=0 and C=N, most commonly when the trapping reagent for the silene is either an aldehyde, ketone, or imine. In many... 

Raasch, and Schaumann and co-workers, have studied the reactions of bis (trifluoromethyl)thioketene (83 R1 = CF3) with alkenes, with thioketones, and with carbodiimides or Schiff-base imines. The products were, respectively, thietans, 1,3-dithietans (84 R1 = CF3), and 1,3-thiazetidines (85 R1 = CF3) (from the carbodiimide).114,115 With phenyl azide the 1,2,3,4-thiatriazoline (86 R = CF3) is formed subsequent pyrolysis yields2,l-benzisothiazole.114... 

The photoelimination of carbon dioxide from esters and lactones is a process that has been the subject of detailed investigations. Discussion here is limited to nitrogen containing systems. 3,4-Diphenylsydnone (464), on irradiation in benzene, is converted via the nitrile imine 465 into 2,4,5-triphenyl-1,2,3-triazole (466)388 initial bond formation between N-2 and C-4 followed by loss of carbon dioxide to give the diazirine 467 is proposed to account for the formation of the nitrile imine. Nitrile imines generated in this way have been trapped with alkenes and alkynes to give pyrazoles389... 

In addition to cydocondensation reactions of the Paal-Knorr type, cycloaddition processes play a prominent role in the construction of pyrrole rings. Thus, 1,3-dipo-lar cycloadditions of azomethine ylides with alkene dipolarophiles are very important in the preparation of pyrroles. The group of de la Hoz has studied the micro-wave-induced thermal isomerization of imines, derived from a-aminoesters, to azomethine ylides (Scheme 6.185) [346]. In the presence of equimolar amounts of /i-nitrostyrenes, three isomeric pyrrolidines (nitroproline esters) were obtained under solvent-free conditions in 81-86% yield within 10-15 min at 110-120 °C through a [3+2] cycloaddition process. Interestingly, using classical heating in an oil bath (toluene reflux, 24 h), only two of the three isomers were observed. 

The TEAF system can be used to reduce ketones, certain alkenes and imines. With regard to the latter substrate, during our studies it was realized that 5 2 TEAF in some solvents was sufficiently acidic to protonate the imine (p K, ca. 6 in water). Iminium salts are much more reactive than imines due to inductive effects (cf. the Stacker reaction), and it was thus considered likely that an iminium salt was being reduced to an ammonium salt [54]. This explains why imines are not reduced in the IPA system which is neutral, and not acidic. When an iminium salt was pre-prepared by mixing equal amounts of an imine and acid, and used in the IPA system, the iminium was reduced, albeit with lower rate and moderate enantioselectivity. Quaternary iminium salts were also reduced to tertiary amines. Nevertheless, as other kinetic studies have indicated a pre-equilibrium with imine, it is possible that the proton formally sits on the catalyst and the iminium is formed during the catalytic cycle. It is, of course, possible that the mechanism of imine transfer hydrogenation is different to that of ketone reduction, and a metal-coordinated imine may be involved [55]. 

The formation of the primary carbocation can be achieved by treatment of an alkene or an epoxide with a Bronsted or a Lewis add, by elimination of water from an alcohol or an alcohol from an acetal and by readion of enones and imines with Lewis acids. The two latter reactions may also be classified under anionic domino reactions depending on the following steps. 

A rationalization of the generally selective formation of the undesired C-16 -C-14 PREF relative stereochemistry on reaction of the chloro-imine-chloroindoline alkene 17a,b with vindoline (3) may be found in a preferred conformation, 25a or 25b, of the cationic intermediate 25, where the C-3 methylene group hinders approach to one face of the nine-mem-bered ring (Fig. 2). A conformationally more flexible nine-membered ring cationic intermediate 29a,b would be expected to be formed from the chloro derivative of a D-secocleavamine 30. From reaction of such a compound with vindoline (3), under the usual protic acid conditions for cou-... 

The aza-Diels-Alder reaction is an important and versatile tool for the preparation of nitrogen-containing heterocycles present in numerous natural products and drug candidates. It involves the [4 + 2] cycloaddition of either an imine with an electron-rich diene or an azabutadiene with an electron-rich alkene (inverse electron demand). Catalytic asymmetric variants employing not only metal complexes, but also organic molecules were disclosed over the last few years. 

Extensive studies on diastereoselectivity in the reactions of 1,3-dipoles such as nitrile oxides and nitrones have been carried out over the last 10 years. In contrast, very little work was done on the reactions of nitrile imines with chiral alkenes until the end of the 1990s and very few enantiomerically pure nitrile imines were generated. The greatest degree of selectivity so far has been achieved in cycloadditions to the Fischer chromium carbene complexes (201) to give, initially, the pyrazohne complexes 202 and 203 (111,112). These products proved to be rather unstable and were oxidized in situ with pyridine N-oxide to give predominantly the (4R,5S) product 204 in moderate yield (35-73%). 

The use of chiral azomethine imines in asymmetric 1,3-dipolar cycloadditions with alkenes is limited. In the first example of this reaction, chiral azomethine imines were applied for the stereoselective synthesis of C-nucleosides (100-102). Recent work by Hus son and co-workers (103) showed the application of the chiral template 66 for the formation of a new enantiopure azomethine imine (Scheme 12.23). This template is very similar to the azomethine ylide precursor 52 described in Scheme 12.19. In the presence of benzaldehyde at elevated temperature, the azomethine imine 67 is formed. 1,3-Dipole 67 was subjected to reactions with a series of electron-deficient alkenes and alkynes and the reactions proceeded in several cases with very high selectivities. Most interestingly, it was also demonstrated that the azomethine imine underwent reaction with the electronically neutral 1-octene as shown in Scheme 12.23. Although a long reaction time was required, compound 68 was obtained as the only detectable regio- and diastereomer in 50% yield. This pioneering work demonstrates that there are several opportunities for the development of new highly selective reactions of azomethine imines (103). 

The cycloaddition reactions of isoquinolinium species produce fused isoquinoline products. The Af-ylide of 53, formed with base addition, couples with alkenes <99S51> or imines <99T7279> to afford tricyclic products, such as 54. Pyrrole-fused isoquinolines result from the reaction between mUnchnone imine intermediates and a,yff-ethylenic esters <99EJOC297>. N-Arylimides undergo 1,3-dipolar cycloaddition with strained frani-cyclooctenes, as opposed to common cycloalkenes, to tdford the pyrazolidine-fused ring system <99H(50)353>. 

Similar catalytic asymmetric approach has been successfully used in the reaction of a sulfonium ylide with electron-deficient imines" " and alkenes," " giving aziridines 135 and cyclopropane 136 with high enantioselectivity, respectively (Scheme 15). 

In addition to copper and rhodium catalysts commonly used in the generation of metal carbene complexes, other transition metals have also been explored in the diazo decomposition and subsequent ylide generation.Che and co-workers have recently studied ruthenium porphyrin-catalyzed diazo decomposition and demonstrated a three-component coupling reaction of a-diazo ester with a series of iV-benzylidene imines and alkenes to form functionalized pyrrolidines in excellent diastereoselectivities (Scheme 20). ... 

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